Preparation of n-substituted 2-aminophenyl aryl ketone

ABSTRACT

A process for preparing intermediates useful in the preparation of diazepam and oxazepam type psycoleptic 1,4-benzodiazepines is described, which involves replacing in hydroxyaminoacetic acid, the hydrogen of the hydroxyl group attached to nitrogen and the hydrogen directly attached to nitrogen with acetyl groups, replacing the hydroxyl group attached to the carbonyl carbon with chlorine, and condensing the product with a 2-aminobenzophenone.

United States Patent McCaully et al.

151 3,691,235 51 Sept. 12, 1972 1 PREPARATION OF N-SUBSTITUTED 2- AMINOPHENYL ARYL KETONE [72] Inventors: Ronald J. McCaully, Malvern; Stanley C. Bell, Philadelphia, both of Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: June 29, 1965 [21] Appl. No.: 468,030

Related US. Application Data [63] Continuation-impart of Ser. No. 395,807, Sept.

11, 1964, abandoned.

[52] US. Cl ..260/545 R, 260/239.3, 424/315,

260/544 Y [51] Int. Cl ..C07c 135/00 [58] Field of Search ..260/534 0, 562 P, 545

[56] References Cited UNITED STATES PATENTS 10/1965 Schenker et a]. ..260/544 X 2/1964 Milionis et a1 ..260/662 P FOREIGN PATENTS OR APPLICATIONS 1,320,265 1/1963 France ..260/534 0 OTHER PUBLICATIONS Saucy et al.; Helv. Chim. Acta., Vol. 45, pages 2,226- 2,241 (1962).

Tsezen; Zhur. Obshch. Khim., Vol. 32, pages 3,290- 3,294 (1962).

Primary Examiner-Lorraine A. Weinberger Assistant ExaminerRobert Gerstl AttorneyVito Victor Bellino [5 7] ABSTRACT 2 Claims, 1 Drawing Figure PATENTEDSEP 12 I972 INVENTORS RONALD J. McCAULLY STANLEY c. BELL BY V JM V/Jn ATTORNEY PREPARATION OF N-SUBSTITUTED 2- AMINOPHENYL ARYL KETONE This application is a continuation-in-part of Ser. No. 395,807, filed 1964 September 1 1 now abandoned.

This invention relates to process for making compositions of matter classified in the art of chemistry as substituted 2-aminophenyl aryl ketones and to intermediates for their production.

The invention sought to be patented in a principal process aspect resides in the concept of a sequence of reactions including: simultaneously replacing the hydrogen of the hydroxyl group attached to nitrogen, and the hydrogen directly attached to nitrogen in hydroxyaminoacetic acid with acetyl groups, replacing the hydroxyl group attached to carbonyl with a chlorine, and condensing the product so-obtained with 2-aminobenzophenone.

The invention sought to be patented in its principal composition aspect is described as residing in the concept of a chemical compound in which the hydrogen atom of the hydroxyl group attached to nitrogen and the hydrogen atom attached directly to the nitrogen atom of hydroxyaminoacetic acid, have been replaced with acetyl groups.

The tangible embodiments of the principal composition aspect of the invention, reveal upon infra-red spectrographic analysis, spectral data confirming the molecular structure hereinbefore set forth. Thus the amide carbonyl, the ester carbonyl, and the acid carbonyl are evident. The aforementioned physical characteristics taken together with the nature of the starting material and the mode of synthesis positively confirms the structure of the composition sought to be patented.

The tangible embodiments of the invention possess the inherent applied use characteristic of being intermediates for the production of valuable 1,3-dihydro-5- phenyl-ZH-l,4-benzodiazepin-2-ones which have useful properties in that they are valuable for human medicinal uses, having demonstrated activity as anticonvulsants, sedatives, and muscle relaxants. Diazepam (sold commercially as Valium) is a compound having this structure. Moreover the specific compositions, 2- [2-(N-acetoxyacetamido)-acetamido]-5- chlorobenzophenone produced by the process of the invention, exhibits sedative activity when tested according to standard pharmacological procedures.

The invention sought to be patented in a second principal composition aspect is described as residing in the concept of a chemical compound in which the hydrogen atom of the hydroxyl group attached to nitrogen and the hydrogen atom attached directly to the nitrogen atom of hydroxyaminoacetic acid, have been replaced with acetyl groups and the hydroxyl group attached to carbonyl has been replaced with chlorine.

The tangible embodiments of the second principal composition aspect of the invention, reveal upon nuclear magnetic resonance analysis, spectral data confirming the molecular structure hereinbefore set forth. Thus the nuclear magnetic resonance spectrum is devoid of acidic protons. The aforementioned physical characteristic taken together with the nature of the described in the chemical literatures.

Caution: llydroxyaminoacetic acid and its low molecular weight derivatives such as Z-(N-acetyl-N- starting material and the mode of synthesis positively acetoxyamino)acetic acid and 2-(N-acetyl-N-acetoxyamino)acetyl chloride are unstable and their decomposition is auto-catalytic. In view of their hazardous nature care must be taken in handling them and the precautions known to those skilled in the art of explosives should be observed.

Acylation of hydroxyaminoacetic acid (I) with an excess of an acylating agent, such as, but not limited to acetic anhydride, acetyl chloride, isopropenyl acetate or ketene, under mild conditions, i.e. at from room temperatures to about 60'70 C., produces a compound in which the active hydrogen of the hydroxyl group attached to nitrogen and the active hydrogen attached directly to nitrogen are selectively replaced by acyl groups (II), thus serving to protect these otherwise reactive centers until a later stage in the over-all synthesis; more specifically 2-(N-acyl-N-acyloxyamino)acetic acid. The same result may be achieved under more strenuous conditions if an excess of acid corresponding to the acylating agent is used as a solvent; since the presence of such excess acid prevents the reaction from proceeding beyond the diacylation stage. The acylation also may be carried out in a solvent such as methylene chloride or 1,2-dimethoxyethane. If a solvent is used, it isapparent to one skilled in the art of organic chemistry that it should be one which will not itself react with the acylating agent. For optimum results however no solvent is necessary and the reaction is carried out under milditemperature conditions, i.e.,the reaction mixture is heated to 50 C. and maintained at that temperature for approximately 15 minutes. While, asindicated, some heat is desirable for optimum yield, extended excessive heating will cause decomposition and should be avoided.

Unreacted acylating agent is removed by distillation under reduced pressure. The resulting residue is first dissolved in a medium which will not interfere with the subsequent reaction to replace hydroxy by a carboxyl activating group, such as methylene chloride or ethylene dichloride, and the N,N-diacylatedaminoacetic acid is treated witha reagent such as thionyl chloride, phosphorus pentachloride or phosphorus pentabromide, which will replace the .hydroxyl group attached to carbonyl with a group which activates'the carbonyl, such as the corresponding halide. The reaction mixture is permitted to reflux at the boiling point of the solvent in an atmosphere of nitrogen for about 5 minutes. The solvent and excess halogenating agent are removed under vacuum, and'the residue,.an N-acyloxy- N-acylacetyl halide (III), is added :to .2-aminobenzophenone, preferably in a non-reactive solvent such as methylene chloride, benzene, or toluene, to produce 2- [N-acyl-N-acyloxyaminoacetamido]benzo-phenone (IV).

It will be apparent to one skilled in the art of organic chemistry that in addition to the method hereinbefore described, in which the Z-aminobenzophenone is reacted with 2-(N-acyl-N-acyloxyaminoacetyl)- halide the same product is obtained if the N,N-diacylatedaminoacetic acid instead of being converted to the corresponding acyl halide, is condensed with the 2- aminobenzophenone in the presence of a condensing agent such as carbodiimide, ethoxyacetylene, and the like.

Alternatively, using excess acylating agent and more strenuous conditions, hydroxyaminoacetic acid is triacylated to produce a diacylated mixed anhydride, namely the mixed anhydride corresponding to the acylating agent used and Z-(N-acyI-N-acyloxyamino)acetic acid (VI). Reaction of this compound with Z-aminobenzophenone is as hereinbefore described for the corresponding acyl halide and acid. This alternative using a mixed anhydride however is less desirable because it is wasteful of aminobenzophenone.

It will be apparent from the disclosure herein, to those skilled in the art of organic chemistry, that for the purposes of this invention the protecting acyl group replacing the active hydrogen of the hydroxyl group attached to nitrogen and the active hydrogen directly attached to nitrogen of hydroxyaminoacetic acid, can be any acyl group which does not interfere with the course of the reaction. It can be, for example, an alkanoyl group, such as acetyl, propionoyl, or caproyl, an aroyl, such as benzoyl, naphthoyl, substituted benzoyl, an araliphatic carbonyl group, such as cinnamoyl, a heterocyclic carbonyl group, such as furoyl, pyridinoyl, tosyl group, a carbobenzoxy group, and the like. Such groups, when used for the purposes hereinbefore disclosed, are full equivalents of the invention as particularly claimed and described.

From the disclosure herein it will also be apparent to one skilled in the art of organic chemistry that the group activating the carbonyl can be any activating group which does not interfere with the course of the reaction. It can be, for example, chlorine, or another halogen such as bromine or it can be an acyloxy group formed from an acyl group such as those hereinbefore specifically named and the like. Such groups when used for the purposes hereinbefore disclosed are full equivalents of the invention as particularly claimed and described.

From the disclosure herein illustrating the invention as applied to 2-aminobenzophenones as starting materials, which produce compounds wherein the group attached to carbonyl other than 2-aminophenyl is phenyl, it will be apparent to organic chemists that any mono-hetero mono-cyclic-aryl nuclei can be in the starting material in lieu of phenyl without affecting the course of the reactions. Accordingly, the starting materials wherein the phenyl group is replaced by a 2- or 3-thienyl; 2 or 3-furyl; 3- or 4-pyridyl radical or phenyl substituted with groups such as halogen, trifluoromethyl, lower alkoxy, lower alkyl, and the like are full equivalents for the purposes of the invention.

The following example illustrates the best mode contemplated by the inventors of using the claimed process of the invention and of the manner of making and using a specific embodiment of the claimed compositions of the invention.

Caution: Hydroxyaminoacetic acid and its low molecular weight derivatives such as 2-(N-acetyl-N- acetoxyamino)acetic acid and 2-(N-acetyl-N-acetoxyamino)acetyl chloride are unstable and their decomposition is auto-catalytic. In view of their hazardous na ture care must be taken in handling them and the precautions known to those skilled in the art of explosives should be observed.

7 EXAMPLE 1 Add hydroxyaminoacetic acid (1.00 g.) to 15 ml. of acetic anhydride and agitate under a nitrogen atmosphere for 15 minutes. Maintain the reaction mixture at 50 C. Filter to separate unreacted acid and remove the solvent from the filtrate until a yellow oil is obtained. Disperse the oil in a small amount of toluene and remove the toluene in vacuo to toluene vapor distil off unreacted acetic anhydride. Repeat until crystalline 2-(N-acetyl-N-acetoxyamino)acetic acid is obtained. Dissolve the acid in a solution of 3 ml. of thionyl chloride in 10 ml. of methylene chloride. Heat the solutionfor 5 minutes at reflex temperature in a nitrogen atmosphere. Remove the solvent and excess thionyl chloride by evaporation in vacuo to obtain 2- (N-acetyl-N-acetoxyamino)acetyl chloride (n.m.r. spectrum is devoid of acidic protons and exhibits absorption at 2.11 8 (3 protons), 2.24 8 (3 protons) and 4.80 6 (2 protons)). Add the acyl chloride dissolved in 20 ml. methylene chloride to a solution of 2.14 g. of 2- amino-5-chlorobenzophenone dissolved in 20 ml. of methylene chloride. Stir the reaction mixture for 30 minutes at 27 then heat to reflux and stir for 10 minutes. Remove the solvent in vacuo, triturate the residue with ethanol and filter to obtain 2-[2-(N- acetoxy-acetamido)acetamido]-5- chlorobenzophenone, 2.6 g. (72% yield), m.p. l50 152 C.

The following examples further illustrate the process of the invention and the method for preparing the compositions of the invention.

EXAMPLE 2 Warm a mixture of hydroxyaminoacetic acid (200 mg.) and 10 ml. acetic acid anhydride on a steam bath for 15 minutes and then concentrate the resulting solution on a rotary evaporator under reduced pressure.

Dissolve the oily residue in 5 ml. 1,2-dimethoxyethane EXAMPLE 3 To hydroxyaminoacetic acid (2.0 g.) slurried in 30 ml. glacial acetic acid, add 5.3 ml. of acetic anhydride. Heat the mixture at 50 C. for 25 minutes under a nitrogen atmosphere with stirring. Remove the solvent under reduced pressure. Extract the soluble material from the residue with 75 ml. of hot ether. Filter out the undissolved amphorous material and allow to cool. 2-

N-Acetyl-N-acetoxyaminoacetic acid crystallizes in the form of colorless needles, mp. ll-l 13 C. The infrared spectrum of the product exhibits carbonyl absorption at 5.59, 5.85, and 6.0l a. The nuclear magnetic resonance spectrum shows methyl singlets at 2.10 and 2.22 and a methylene singlet at 4.45.

EXAMPLE 4 Disperse 2-(N-acetyl-N-acetoxyamino)acetic acid (1.0 g.) in 40 ml. of methylene chloride and add 1.5 g. of phosphorus pentachloride while maintaining the temperature at 5 C. Stir the mixture for 30 minutes at 5 C. after the addition is complete. Allow to settle and decant the supernatent liquid, which contains the,

EXAMPLE 7 in a (2 l.) three-neck flask fitted with stirrer, thermometer, nitrogen inlet, powder ,funnel, and reflux condenser, heat to'65 C. amixture of (208 ml.; 225 g., 2.2 moles) of acetic anhydride and (5 ml.) of glacial acetic acid :under a nitrogen atmosphere. Then add rapidly at 63-65 C. (27.3 g.,'0.30.mole) of N-hydroxyaminoacetic acid with stirring; very slightheat of reac tion is observed.

When the hydroxyaminoacetic acid has reacted as shown by a clear solution-(approximately"l5 minutes) add 63.8 g., 0.70 mole of N-hydroxyaminoacetic acid chloride-ethanol mixture to obtain crystalline 2-N- v acetyl-N-acetoxyaminoacetamido)-5- chlorobenzophenone (0.8 g.), m.p. l49l5 1 C.

EXAMPLE 5 Heat a mixture of 1.0 g. hydroxyaminoacetic acid and ml. of acetyl chloride at reflux for 3 hours. Remove excess acetyl chloride by evaporation under reduced pressure. Dissolve the residue inmethylene chloride and add it to a solution of 2.31 g. of 2-amino- 5-chlorobenzophenone dissolved in methylene chloride. Stir for 15 minutes, remove the solvent under reduced pressure, and recrystallize from absolute ethanol to obtain 0.8 g. of Z-[N-acetoxyacetamidoacetamido]-5-chlorobenzophenone,m.p. l45l47 C.

EXAMPLE 6 Add N-hydroxyaminoacetic acid (9.1 l g., 0.10 mole) to a solution of 22.5 g. (0.22 mole) of acetic anhydride in 30 ml. of ethylene dichloride at 30. Heat the mixture at 65 with stirring for 1.5 hour, cool the amber liquid to and treat dropwise with 33 ml. (53.5 g., 0.45 mole) of thionyl chloride. Maintain the temperature of the reaction mixture at 25 during the addition and then elevate slowly to 45 for 15 minutes. Concentrate the orange solution in vacuo; wash the residual oil 3 times with petroleum ether, treat with benzene, and reconcentrate in vacuo. Dissolve the residue to 90 ml. benzene and add to a solution of 19.5 g. (0.084 mole) 2-amino-5-chlorobenzophenone in 90 ml. of benzene. Stir the mixture for 1 hour at 25. Add anhydrous sodium acetate (6.9 g.) to the mixture and continue stirring for 1 hour. Concentrate the mixture in vacuo, treat with 300 ml. ethanol 28, and reconcentrate in vacuo. Treat the residue with 80 ml. ethanol 2B and chill to 5 for 5 hours. An off-white solid separates which is filtered and washed with ethanol and water to give 21.5 g. (66%) of 2-(N-acetyl-N-acetoxyaminoacetamido)-5-chlorobenzophenone, m.p. lS0-15 1 C.

in small portions at 63'65 C..asv fastas it'reacts; occasionalcooling is required and the addition requires 50 minutes. After allowing the clear red=brown reaction mixture to stir ,at 63-6'5 C. for an additional 15 minutes, cool to 25-30 C. under nitrogen and add 300 ml. of methylenechloride.

To the clear-solution,adddropwiseover 35 minutes (242 ml., 394, g., 3.3 moles) of-.thionyl chloride; during the addition,.evolution of 'HClcoolsthemixture and considerable heat is requiredto'maintain the temperature at 15-25 C.

When I the addition, is complete, heat the solution to reflux (35 minutes) and maintain a gentle reflux (4l-4 4 C.)-for-l5 minutes.-Cool theturbid, red solution to 2030 C. under nitrogen and concentratewith stirring under vacuum in a 50water bath-until no more distils at 1.20 mm. pressure-and the. internal temperature. rises to 45 C. to removeacetyl chloride-thionyl chloride, HCl S0 and methylene chloride Wash the fluid residue three times with hexane (250 ml.) under a:nitrogen-atmosphere, each timestirring well, allowing to settle, andremoving the top hexane layer by suction.

Dissolve the residue'in 3-50-ml.wof-benzene and decant from asmall quantity of tarrymaterial. Add this solution with stirring under a nitrogen atmosphere toa suspension of (195 g., 0.84 mole) 2-amino5- chlorobenzophenone in 550 ml. of benzene at 15 -l8 C.; heat-of-reaction requires ice-bath cooling, particularly during the first two-thirds of the addition; the addition requires 10 minutes.

lf crystallization has notbegun when the addition is complete, seed the mixturewith Z-(N-acetyl-N-acetoxyamino-acetamido)-5-chlorobenzophenone; crystallization begins within 5 minutes. After stirring at 15-l8 C. for 1.5 hour, add g. of anhydrous sodi um acetate. Allow to stir over night at l8-25 C.

Cool the mixture to 8l0 C. and allow to stir for at least one hour. Collect the .pale tan-colored crude by filtration and wash with ml. of coldethanol 28. Wash the wetcrude by stirring for 10 minutes in 480 ml. of ethanol 28 at 20-25 C. and filtering. Re-wash the wet crude to remove sodium acetate, and chloride by stirring in 1,500 ml. of water for 10 minutesat l525 C., filtering,. and drying the cream-colored product in a vacuum at 35-40'C. to obtain 2-(N- acetyl-N-acetoxyamino-acetamido)-5- chlorobenzophenone 188 g. (as a crude product m.p. l42l47 C.).

The subject matter which the applicants regard. as their invention is particularly pointed out and distinctly claimed as follows:

1 The process for preparing a 2- aminobenzophenone of the structure -CHa mi, N

Ulla Nll (l wherein R is an alkyl, alkoxy, halo, nitro, trifluoromethyl group; and

R is hydrogen or an alkyl, alkoxy, halo trifluoromethyl group;

comprising: (a) replacing the hydrogen of the hydroxyl group attached to nitrogen, and the hydrogen directly attached to nitrogen in hydroxyaminoacetic acid. with acetyl groups by reacting hydroxyaminoacetic acid with at least twice the molar equivalent of an acetylating agent at a temperature of below about C., (b) forming the acyl chloride of the product of step (a) by replacing the hydroxyl group attached to carbonyl with a chlorine group at a temperature below about 70 C., and (c) reacting the diacylated amino acetyl halide wherein R and R are as above.

2. The process of claim 1 wherein R is chlorine and R is hydrogen. 

2. The process of claim 1 wherein R is chlorine and R1 is hydrogen. 